Research Statement
I am captivated by the interactions between organisms and how features of one can stimulate a response in another. I study this through the lens of the host-microbe interaction using a synthesis of techniques and approaches from cell biology, microbiology, immunology, development, genetics, and more. My Ph.D. thesis work in the lab of Dr. David Tobin has centered around the host angiogenesis response, which is the process by which new blood vessels emerge from the existing vascular bed to provide additional oxygen to sites of damage. This is a sophisticated and widespread phenomenon that occurs in solid tumor cancers, in response to wounds and burns, in a variety of autoimmune disorders, and in infectious diseases. Notably, this process of angiogenesis has been described in the context of human tuberculosis for many decades, but until recently very little has been done to understand the functional consequences of these new blood vessels that grow to encase the granuloma that surrounds the bacteria.
To enable real-time in vivo observations of the process of tuberculosis pathogenesis, our lab and others use the zebrafish-Mycobacterium marinum model of infection. This model replicates key features of human tuberculosis in a genetically tractable and optically transparent model system. Critically, this model demonstrates the potent angiogenic response typical of human tuberculosis, allowing me to dissect out some of the signaling mechanisms that drive this process. I have been especially interested in filling in our gaps in knowledge as to how host macrophages direct the production of the angiogenic chemokine VEGF downstream of the detection of the mycobacterial lipid trehalose 6-6'-dimycolate (TDM).
Through the application of a combination of zebrafish infection and cell culture models, we identified the previously uncharacterized NFAT signaling pathway in the induction of host angiogenesis. This pathway, well known for its role in T cell development, has rather few known roles in innate immunity and even fewer in the context of tuberculosis. We identified a macrophage-specific role for this pathway in the induction of angiogenesis by TDM through the use of a novel transgenic line that suppresses NFAT signaling solely in macrophages. We further characterized the role of this pathway in response to live infection and in the context of mature, necrotic granulomas and found similar effects. This highly novel finding expands our understanding of the sophisticated ways that mycobacteria seek to manipulate their hosts while also implicating an new pathway in the host immune response to tuberculosis. This work may lead to novel approaches to the treatment of tuberculosis by narrowing in on more specific and targeted methods for targeting bacterially beneficial host processes.
Future Projects
My future research interests are highly varied across the fields I have spent my academic career studying and include critical projects in both cell biology and microbiology.
A recent presentation from the International Zebrafish Disease Models meeting, held virtually over Zoom in October 2021:
ZDMTalkRecording_110521.mp4